Cancer Immunology, Immunotherapy

, Volume 60, Issue 10, pp 1447–1460 | Cite as

Pilot trial of interleukin-2 and zoledronic acid to augment γδ T cells as treatment for patients with refractory renal cell carcinoma

  • Joshua M. Lang
  • Mahazarin R. Kaikobad
  • Marianne Wallace
  • Mary Jane Staab
  • Dorothea L. Horvath
  • George Wilding
  • Glenn Liu
  • Jens C. Eickhoff
  • Douglas G. McNeel
  • Miroslav Malkovsky
Original article

Abstract

Prior to the advent of VEGF-targeted therapies, renal cell carcinoma (RCC) was among the few solid tumors shown to respond to cytokine-based therapies such as interleukin-2 (IL-2) and interferon alpha. Previous work has shown that aminobisphosphonates, including zoledronic acid (ZA), are capable of activating human Vγ9 Vδ2 T cells in vitro, and these cells can be further expanded with IL-2. Moreover, these Vγ9 Vδ2 T cells have cytolytic activity in vitro to multiple human tumor cell lines. In the current report, we have conducted a pilot trial in patients with metastatic RCC, evaluating different doses of ZA in combination with low-dose IL-2 to determine whether combining these agents can promote in vivo proliferation of Vγ9 Vδ2 T cells and elicit an antitumor response. In 12 patients evaluated, no objective clinical responses were observed by RECIST criteria; however, two patients experienced prolonged stable disease. A modest increase in Vγ9 Vδ2 T-cell frequency could be detected by Day 8 of therapy in four of the nine patients who received at least one cycle of therapy, but not to the magnitude anticipated from preclinical models. Repeated administration of IL-2 and ZA resulted in both a diminished in vivo percentage of Vγ9 Vδ2 T cells as well as impaired expansion in vitro after the first cycle of therapy. These results suggest that repeated administration of IL-2 and ZA, at the doses and schedules used in this trial, may actually inhibit the proliferative capacity of Vγ9 Vδ2 T cell in patients with metastatic RCC.

Keywords

Vγ9 Vδ2 lymphocyte Interleukin-2 Zoledronic acid Renal cell carcinoma 

Notes

Acknowledgments

We would like to thank Beth A. Fredricks for her invaluable technical assistance. This work was supported by an investigator-initiated award from Novartis Pharmaceuticals and by the University of Wisconsin Carbone Cancer Center Core Grant P30 CA014520. Dr. Lang is supported by NIH grant T32 CA009614.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Joshua M. Lang
    • 1
  • Mahazarin R. Kaikobad
    • 2
  • Marianne Wallace
    • 2
  • Mary Jane Staab
    • 3
  • Dorothea L. Horvath
    • 3
  • George Wilding
    • 1
  • Glenn Liu
    • 1
  • Jens C. Eickhoff
    • 4
  • Douglas G. McNeel
    • 1
    • 5
  • Miroslav Malkovsky
    • 2
  1. 1.Department of Medicine, Division of Hematology/OncologyUniversity of WisconsinMadisonUSA
  2. 2.Department of Medical Microbiology and ImmunologyUniversity of WisconsinMadisonUSA
  3. 3.Carbone Cancer CenterUniversity of WisconsinMadisonUSA
  4. 4.Department of Biostatistics and Medical InformaticsUniversity of WisconsinMadisonUSA
  5. 5.7007 Wisconsin Institutes for Medical ResearchMadisonUSA

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